We thank Dr. Schroeder for his comments on our paper. We agree with Dr. Schroeder that some children may have bacteriuria even when they are asymptomatic. We disagree, however, on the prevalence and clinical implications of this finding.
Schroeder states that 1.4% of children have asymptomatic bacteriuria, and because the prevalence of UTI among those tested is low (~5%), a large proportion of children with apparent UTIs actually may have asymptomatic bacteriuria and are therefore being misdiagnosed. However, closer reading of the original papers describing the asymptomatic bacteriuria (using a method of urine collection less prone to contamination such as suprapubic aspiration), show that the 1.4% number is the period prevalence of aymptomatic bacteriuria (cumulative over the 12 month follow-up period).1 At any one point in time after 1 month of age, only 0 to 0.4% (see Figure 3 of paper by Wettergren)1 of children tested had asymptomatic bacteriuria (i.e., the point prevalence of asymptomatic bacteriuria was ≤0.4%, and most often 0). Point prevalence represents the value that best reflects the probability of asymptomatic bacteriuria among children presenting to a clinician at one point in time. Furthermore, some children with asymptomatic bacteriuria go on to develop symptoms of UTI making the number of truly misdiagnosed children even smaller. For these reasons, the magnitude of potentially misdiagnosed cases is much smaller than that portrayed by Dr. Schr...

We thank Dr. Schroeder for his comments on our paper. We agree with Dr. Schroeder that some children may have bacteriuria even when they are asymptomatic. We disagree, however, on the prevalence and clinical implications of this finding.
Schroeder states that 1.4% of children have asymptomatic bacteriuria, and because the prevalence of UTI among those tested is low (~5%), a large proportion of children with apparent UTIs actually may have asymptomatic bacteriuria and are therefore being misdiagnosed. However, closer reading of the original papers describing the asymptomatic bacteriuria (using a method of urine collection less prone to contamination such as suprapubic aspiration), show that the 1.4% number is the period prevalence of aymptomatic bacteriuria (cumulative over the 12 month follow-up period).1 At any one point in time after 1 month of age, only 0 to 0.4% (see Figure 3 of paper by Wettergren)1 of children tested had asymptomatic bacteriuria (i.e., the point prevalence of asymptomatic bacteriuria was ≤0.4%, and most often 0). Point prevalence represents the value that best reflects the probability of asymptomatic bacteriuria among children presenting to a clinician at one point in time. Furthermore, some children with asymptomatic bacteriuria go on to develop symptoms of UTI making the number of truly misdiagnosed children even smaller. For these reasons, the magnitude of potentially misdiagnosed cases is much smaller than that portrayed by Dr. Schroeder. Of note, the percentage of asymptomatic carriage pales in comparison to its frequency in other pediatric conditions (e.g., 20% rate of asymptomatic carriage for Group A Streptococcus).
Even if some children diagnosed with UTI actually have asymptomatic bacteriuria, with currently available bedside tests, there is no way for the clinician to know this. In our opinion, this reinforces the need for new test(s) to supplement the urine culture. The leukocyte esterase test (or pyuria on urinalysis) is ill-suited to serve this role because: (1) a significant proportion of children with asymptomatic bacteriuria have pyuria (56% in the Wettergren study)1, (2) approximately 10% to 20% of children with UTI do not have pyuria,2 and 3) in our study,3 and in a subsequent study by Lubell,4 the likelihood of observing pyuria varied by the type of uropathogen present. Although a study conducted by Schroeder5 seems to suggest that the sensitivity of pyuria is much higher than previously reported, as we have discussed elsewhere,6 there are several issues with the design of that study that limit its generalizability. Accordingly, the bulk of available data suggests that the inflammatory response to a UTI is complex (dependent on the interaction between pathogen and host), and that the presence or absence of pyuria alone, albeit informative in a large number of cases, is not always an accurate indication of the presence or absence of UTI. Accordingly, we currently do not believe that pyuria – albeit present in most instances -- should be required for a diagnosis of UTI in symptomatic children; this requirement will result in missed cases of true UTI and will slow down the search for better biomarkers for UTI.
Although our previous meta-analysis did not show that delayed treatment leads to scarring, this could have been due to the limitations in the way data on delayed treatment were collected in the various studies included in the meta-analysis.7 Our most recent study,8 in which these data were collected prospectively and consistently, supports the conclusion that a delay in the initiation of antimicrobial therapy and renal scarring are indeed associated.

We agree with the comments made by Dr. Jain that the interpretation of the urinalysis depends on the clinical context. We find such a case-by-case approach to the interpretation of the data preferable to changing the definition of UTI (to require both a positive culture and pyuria). For febrile infants from whom we obtained a catheterized urine sample, our current practice is to send both a urinalysis (UA) and a urine culture. If the urine culture is positive and the urinalysis is negative, we usually try to obtain a second urine sample if possible. However, in most cases, because fever is present, we end up prescribing antimicrobials to such children. Although a small proportion of the children we treat with antibiotics may indeed have asymptomatic bacteriuria, it is most likely they have a true UTI.

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In the post-HIB, post-pneumococcal immunization era, urinary tract infections (UTIs) are the most common serious bacterial infection (SBI) in infants and young children. The diagnosis of UTI is challenging in this population and has received much attention, including a 2011 AAP clinical practice guideline on diagnosis and management of UTI in febrile infants and young children.1 Shaikh et al’s recent article in Pediatrics on the association between uropathogens and pyuria and the accompanying commentary by Aaron Friedman support the importance of a urine culture even in the absence of a negative urinalysis (UA).2,3 On the other hand, Schroeder et al (Pediatrics 2015) find that in infants <3 months with a true UTI, UA sensitivity is higher than previously reported for UTI, suggesting that the UA is reliable even in young infants.4 What is a clinician to do?

As Dr Lewis First suggests in his commentary, let’s look at the context.5 The discrepancy regarding the utility of a UA as a screening test for UTI may be due to the different populations that these studies are addressing. Shaikh et al evaluated children with ‘symptoms consistent with a diagnosis of a UTI’ in whom it would make sense to have a high index of suspicion even with a negative UA and perhaps have a lower threshold for starting antibiotics pending urine culture results, which should always be obtained. Such an approach may be too conservative in a well appearing (likely not bacteremic) patie...

In the post-HIB, post-pneumococcal immunization era, urinary tract infections (UTIs) are the most common serious bacterial infection (SBI) in infants and young children. The diagnosis of UTI is challenging in this population and has received much attention, including a 2011 AAP clinical practice guideline on diagnosis and management of UTI in febrile infants and young children.1 Shaikh et al’s recent article in Pediatrics on the association between uropathogens and pyuria and the accompanying commentary by Aaron Friedman support the importance of a urine culture even in the absence of a negative urinalysis (UA).2,3 On the other hand, Schroeder et al (Pediatrics 2015) find that in infants <3 months with a true UTI, UA sensitivity is higher than previously reported for UTI, suggesting that the UA is reliable even in young infants.4 What is a clinician to do?

As Dr Lewis First suggests in his commentary, let’s look at the context.5 The discrepancy regarding the utility of a UA as a screening test for UTI may be due to the different populations that these studies are addressing. Shaikh et al evaluated children with ‘symptoms consistent with a diagnosis of a UTI’ in whom it would make sense to have a high index of suspicion even with a negative UA and perhaps have a lower threshold for starting antibiotics pending urine culture results, which should always be obtained. Such an approach may be too conservative in a well appearing (likely not bacteremic) patient with fever without localizing source with a low suspicion of UTI (based on low assessment of UTI risk), in whom a negative urinalysis is likely to be reassuring by itself. The 2011 AAP practice guideline has it spot on in recommending that a negative UA may be sufficient if antibiotics are not planned in a well appearing patient with fever without source. However, if ill appearing and/or if antibiotics are planned, a reliable urine culture must be obtained. Finally, the clinical practice guideline recommends that to establish a diagnosis of UTI, both a UA and urine culture are required. This CPG addresses a very common clinical scenario in pediatrics (evaluation of the most common SBI in children with fever) continues to be a helpful resource for pediatric clinicians.

I read with interest the manuscript by Shaikh et al1 on the association between pyuria and uropathogen type in children being evaluated for urinary tract infection (UTI). Their conclusion differs from our related investigation2 in Pediatrics, where we concluded that the sensitivity of the urinalysis (UA) has been previously underestimated due to a faulty gold standard, namely, urine cultures that are falsely positive because of contamination and asymptomatic bacteruria (AB). In our sample of young infants with bacteremic UTI, a condition that cannot be explained by contamination or AB, 99.5% of subjects had a UA that was positive for either leukocyte esterase or pyuria (≥ 3 wbc/hpf).2 The accompanying commentary to our article concluded that “the absence of pyuria should create great doubt about the presence of a UTI.”3

In this recent investigation, Shaikh et al1 present data consistent with prior reports that pyuria on the UA is imperfectly sensitive, and provide new information suggesting that the sensitivity might differ by uropathogen. They report that the sensitivity of pyuria of only 90% cannot be explained by AB, because the prevalence of AB is “too low (<1%)”. The actual prevalence of AB (detected via suprapubic aspirate) in the study by Wettergren that the authors cite in making this claim is 1.4%: 0.9% in girls and 2.5% in boys.4 Nonetheless, even a prevalence of AB as low as 1% could have a substantial impact on the apparent sensitivity of the UA. In...

I read with interest the manuscript by Shaikh et al1 on the association between pyuria and uropathogen type in children being evaluated for urinary tract infection (UTI). Their conclusion differs from our related investigation2 in Pediatrics, where we concluded that the sensitivity of the urinalysis (UA) has been previously underestimated due to a faulty gold standard, namely, urine cultures that are falsely positive because of contamination and asymptomatic bacteruria (AB). In our sample of young infants with bacteremic UTI, a condition that cannot be explained by contamination or AB, 99.5% of subjects had a UA that was positive for either leukocyte esterase or pyuria (≥ 3 wbc/hpf).2 The accompanying commentary to our article concluded that “the absence of pyuria should create great doubt about the presence of a UTI.”3

In this recent investigation, Shaikh et al1 present data consistent with prior reports that pyuria on the UA is imperfectly sensitive, and provide new information suggesting that the sensitivity might differ by uropathogen. They report that the sensitivity of pyuria of only 90% cannot be explained by AB, because the prevalence of AB is “too low (<1%)”. The actual prevalence of AB (detected via suprapubic aspirate) in the study by Wettergren that the authors cite in making this claim is 1.4%: 0.9% in girls and 2.5% in boys.4 Nonetheless, even a prevalence of AB as low as 1% could have a substantial impact on the apparent sensitivity of the UA. In the Shaikh et al study, for example, the estimated prevalence of UTI was ~ 5% (1,394/26,151). If the population prevalence of AB is 1% in children, then an estimated 1/5 positive cultures in their sample will be falsely positive, i.e. a positive urine culture with a negative UA. Therefore, if this population were similar to Wettergren’s, the sensitivity of even a perfect screening test applied to this population would theoretically be ~80%. As long as urine cultures alone are used as a gold standard to define UTI, we are unlikely to ever see UA sensitivities that approach 100%. The fact that sensitivities in this study appear to differ by pathogen could also be explained by the varying likelihoods of certain organisms to colonize the GU tract and/or contaminate a urine sample.

Shaikh et al also reiterate concerns that a delay in the diagnosis of UTI (as might occur if a physician is misled by a negative UA) may increase the risk of renal scarring. However, this concern is belied by data from their own meta-analysis demonstrating that fever > 24 hours before diagnosis of UTI is not associated with renal scarring (odds ratio 1.11, 95% confidence interval 0.72 – 1.71).5

Sincerely,
Alan R. Schroeder, MD
Department of Pediatrics
Stanford University School of Medicine